US4009206A - N-(substituted phenyl and benzyl)abietamides - Google Patents

N-(substituted phenyl and benzyl)abietamides Download PDF

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US4009206A
US4009206A US05/604,308 US60430875A US4009206A US 4009206 A US4009206 A US 4009206A US 60430875 A US60430875 A US 60430875A US 4009206 A US4009206 A US 4009206A
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acid
dihydroabietamide
amide according
grams
amide
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Hiromu Murai
Katsuya Ohata
Hiroshi Enomoto
Kenji Sempuku
Koji Kitaguchi
Yukio Fujita
Yoshiaki Yoshikuni
Kohei Kura
Katsahide Saito
Tamiki Mori
Yasuo Yasutomi
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C233/59—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
    • C07C2603/26—Phenanthrenes; Hydrogenated phenanthrenes

Definitions

  • n an integer of 1, 2, or 3
  • n an integer of 0 or 1
  • this invention relates to anilide and benzylamide derivatives of abietic acid and related compounds and, furthermore particularly, this invention relates to abietanilides (hereinafter referred to as AAN), dehydroabietanilides (DEAN), dihydroabietanilides (DIAN), tetrahydroabietanilides (TAN), abietic acid benzylamide derivatives (ABA), dehydroabietic acid benzylamide derivatives (DEBA), dihydroabietic acid benzylamide derivatives (DIBA), and tetrahydroabietic acid benzylamide derivatives (TBA) and manufacture thereof by the reaction of abietic acid (AA), dehydroabietic acid (DEA), dihydroabietic acid (DIA), tetrahydroabietic acid (TA), and/or active derivatives thereof with a compound of a formula ##STR2## where definitions for X, n, and m are the same as
  • abietic acid series compounds particularly AA which is one of the starting materials according to this invention is contained in large quantities in the resin obtainable from the pine varieties plants and is one of the readily and inexpensively available natural compounds.
  • DEA can also be obtained with high yield by treating the pine variety resin with palladium carbon.
  • DIA and TA can be readily prepared from AA by the use of a suitable reducing agent.
  • active derivatives of abietic acid, etc. means acid anhydride, acid esters, and acid halides.
  • Derivation of acids to such active derivatives can be done by the usual way.
  • acid anhydride is prepared by the use of dehydrating agents such as acetic anhydride and acetyl chloride;
  • acid esters are prepared through the ordinary esterification such as, for example, methyl esterification with diazomethane;
  • acid halides are prepared through halogenation using such compounds as PX 5 , PX 3 , and SOX 2 where X means halogen atom.
  • Aniline and benzylamine compounds (II) are other starting materials in this invention.
  • Examples of such compounds covered by the formula (II) are 2,6-dimethylaniline; 2,4-dimethylaniline; 2,4,6-trimethylaniline; o-ethoxycarbonylaniline; p-methoxycarbonylaniline; 3-hydroxy-4-carboxyaniline; m-trifluoromethylaniline; p-chloroaniline; m-bromoaniline; p-ethoxyaniline; p-methoxyaniline; o-methylbenzylamine; m-methylbenzylamine; p-methylbenzylamine; p-methoxybenzylamine; o-chlorobenzylamine; m-chlorobenzylamine; and p-chlorobenzylamine. It should, however, be understood that this invention is not limited to the use of the above compounds only.
  • Novel compounds (I) according to this invention are prepared by, for example, the method referred to above. If necessary, the reaction may be carried out using a dehydrating agent such as dicycloalkylcarbodiimide or a basic catalyst such as alkali hydroxides, alkoxides, and amides.
  • a dehydrating agent such as dicycloalkylcarbodiimide or a basic catalyst such as alkali hydroxides, alkoxides, and amides.
  • alcohols such as methanol and ethanol, fatty or aromatic hydrocarbons such as n-hexane, benzene and xylene, halogenated hydrocarbons such as chloroform, cyclic ethers such as dioxane and tetrahydrofuran and aromatic heterocyclic compounds represented by pyridine can be used.
  • the reaction may sometimes readily proceed without solvent, and in such case the solvent may be dispensed with.
  • 1.5 to 3 mols of the compound (II) are usually added to one mole of abietic acids of their active derivatives such as acid anhydride, ester and acid halide. If necessary, the acid component is dissolved or suspended in an adequate quantity of a suitable solvent, and the compound (II) is added by small quantities while executing requisite cooling and agitation of the system.
  • the reaction is carried out under a suitable temperature condition, for instance under ice cooling state, at room temperature or under heating, and is usually completed within 12 hours.
  • a suitable temperature condition for instance under ice cooling state, at room temperature or under heating, and is usually completed within 12 hours.
  • the reaction between acid halide and compound (II) is completed at lower temperature within one hour, and this can be readily recognized from the disappearance of spots of material on a silica gel thin layer chromatogram.
  • the intended abietamide derivatives (I) such as AAN, DEAN, DIAN, TAN, ABA, DEBA, DIBA, and TBA can be separated from the reaction product mixture by the usual way.
  • a hydrophilic solvent such as ether and benzene is newly added. Then, the resultant system is washed.
  • a hydrophobic solvent such as benzene and n-hexane is used, the system is directly washed.
  • the washing is made with a 3 to 5 percent dilute acid, if necessary, and then with a 3 to 5 percent dilute alkali and thereafter with water, followed by drying.
  • the residual solvent is removed from the system, whereby crystalline particles as residue are obtained in many cases.
  • purification through re-crystallization is directly made by using a suitable re-crystallizing solvent.
  • the purification is made with alumina or silica gel column chromatography or thin layer chromatography for manufacture.
  • DIA disclosed in the examples is ⁇ 8 -dihydroabietic acid
  • this invention is not limited to the use of it only, but other ⁇ 7 -, ⁇ 13 -, and ⁇ 14 -isomers are, of course, used as well.
  • N-(2,6-dimethylphenyl)- ⁇ 8 -dihydroabietamide was produced in the following way:
  • Acid chloride obtained from 6.1 grams (20 millimols) of ⁇ 8 -DIA and excessive thionyl chloride was cooled to freeze, and then 4.84 grams (20 millimols) of 2,6-dimethylaniline was added.
  • the resultant system was left at room temperature for one hour while intermittently agitating it.
  • 50 millilitres of benzene was added to form a suspension, which was then washed with 5% HCl and then with water.
  • the benzene layer was dried with anhydrous magnesium sulfate, followed by removal of benzene.
  • the resultant crystalline residue was re-crystallized from acetone to obtain 5.2 grams of colorless needle-like crystals (corresponding to a yield of 80 percent) with a melting point of 200° to 202° c.
  • N-(2,6-dimethylphenyl)-tetrahydroabietamide was produced in the following way:
  • Acid chloride obtained from 1.53 grams (5 millimols) of TA and excessive thionyl chloride was added to 10 millilitres of benzene, and to the resultant system 1.82 grams (15 millimols) of 2,6-dimethylaniline was gradually added. Then, the resultant system was continually agitated at room temperature for 2 hours, and then the precipitate was filtered away. Then, the resultant liquid was washed with 5-% HCl and then with water, and then the benzene layer was dried with anhydrous magnesium sulfate.
  • N-(p-ethoxyphenyl)- ⁇ 8 -dihydroabietamide was produced in the following way:
  • N-(p-methoxyphenyl)-abietamide was produced in the following way:
  • N-(p-chlorophenyl)-dehydroabietamide was produced in the following way:
  • the resultant filtrate was concentrated to 40 millilitres, followed by leaving overnight at room temperature. Then the precipitate was filtered away, and the filtrate was concentrated to dry solide. The powdery residue thus obtained was then re-crystallized from ethanol to obtain 3.03 grams of colorless needle-like crystals (corresponding to a yield of 74 percent) with a melting point of 180° to 181.5° C.
  • N-(2-methylbenzyl)- ⁇ 8 -dihydroabietamide was produced in the following way:
  • N-(3-chlorobenzyl)- ⁇ 8 -dihydroabietamide was produced in the following way: Acid chloride obtained from 1.53 grams (5 millimols) of ⁇ 8 -DIA and excessive thionyl chloride was dissolved in 10 millilitres of benzene, and to this solution a solution obtained by dissolving 2.12 grams (15 millimols ) of m-chlorobenzylamine in 10 millilitres of benzene was added under cooling condition. The resultant system was then agitated at room temperature for 3 hours.
  • N-(4-methoxybenzyl)-abietamide was produced in the following way:
  • the ether layer thus formed was then washed with 3-% KOH aqueous solution, water and with 3-% HCI in the mentioned order, and then it is dried with anhydrous magnesium sulfate, followed by removal of ether through filtering.
  • the resultant oily residue was subjected to silica gel column chromatography with chloroform used as solvent to obtain 4.22 grams of glassy substance (corresponding to a yield of 72 percent).
  • N-(2-methylbenzyl)-tetrahydroabietamide was produced in the following way:
  • N-(4-methylbenzyl)-dehydroabietamide was produced in the following way:
  • a completely synthetic diet containing 1% of cholesterol, 0.25% of sodium cholate and 0.0003%, 0.003%, and 0.03% of the test compound is given to a group of 6 male rats having a body weight of about 50 g consecutively for 3 days, and the rats are fasted overnight. Then, the rats are decapitated and blood is collected to determine the cholesterol concentration in blood. The concentration of cholesterol in blood is measured with Technicon Autoanalyzer(Technicon Laboratory: Method File N-24a) Obtained results are shown in Table 1.
  • Each value shown in the Table is a relative value determined based on the supposition that the value of the control group (the cholesterol-administered group) is 0 and the value of the normal group (the non-cholesterol-administered group) is 100.
  • the mark “*" indicates that the value is statistically significant over the control group with a significant level of 5% and the mark "*" indicates that the value is statistically significant over the control group with a significance level of 1%.

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  • Pharmacology & Pharmacy (AREA)
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Abstract

Substituted N-phenyl and N-benzyl abietamide derivatives, including the dehydro-, dihydro-, and tetrahydroabietamide derivatives, are cholesterol lowering agents. The abietamide derivatives, of which N-(2,6-dimethylphenyl)-Δ8 -dihydroabietamide is a typical example, are produced by the reaction of abietic acid, dehydroabietic acid, dihydroabietic acid, tetrahydroabietic acid and/or active derivatives thereof with a substituted aniline or benzylamine.

Description

DETAILED DESCRIPTION OF THE INVENTION
This invention relates to novel abietamide derivatives having a general formula ##STR1## where X = halogen, nitro, lower alkyl, haloalkyl, hydroxyl, lower alkoxy, carboxyl, or carboalkoxy; being the same or different
n = an integer of 1, 2, or 3
m = an integer of 0 or 1
Z = abietic, dehydroabietic, dihydroabietic, or tetrahydroabietic acid residue
And a method of production thereof. More particularly this invention relates to anilide and benzylamide derivatives of abietic acid and related compounds and, furthermore particularly, this invention relates to abietanilides (hereinafter referred to as AAN), dehydroabietanilides (DEAN), dihydroabietanilides (DIAN), tetrahydroabietanilides (TAN), abietic acid benzylamide derivatives (ABA), dehydroabietic acid benzylamide derivatives (DEBA), dihydroabietic acid benzylamide derivatives (DIBA), and tetrahydroabietic acid benzylamide derivatives (TBA) and manufacture thereof by the reaction of abietic acid (AA), dehydroabietic acid (DEA), dihydroabietic acid (DIA), tetrahydroabietic acid (TA), and/or active derivatives thereof with a compound of a formula ##STR2## where definitions for X, n, and m are the same as defined above.
The abietic acid series compounds particularly AA which is one of the starting materials according to this invention is contained in large quantities in the resin obtainable from the pine varieties plants and is one of the readily and inexpensively available natural compounds. DEA can also be obtained with high yield by treating the pine variety resin with palladium carbon. DIA and TA can be readily prepared from AA by the use of a suitable reducing agent.
The term "active derivatives" of abietic acid, etc. means acid anhydride, acid esters, and acid halides. Derivation of acids to such active derivatives can be done by the usual way. For instance, acid anhydride is prepared by the use of dehydrating agents such as acetic anhydride and acetyl chloride; acid esters are prepared through the ordinary esterification such as, for example, methyl esterification with diazomethane; and acid halides are prepared through halogenation using such compounds as PX5, PX3, and SOX2 where X means halogen atom.
Aniline and benzylamine compounds (II) are other starting materials in this invention. Examples of such compounds covered by the formula (II) are 2,6-dimethylaniline; 2,4-dimethylaniline; 2,4,6-trimethylaniline; o-ethoxycarbonylaniline; p-methoxycarbonylaniline; 3-hydroxy-4-carboxyaniline; m-trifluoromethylaniline; p-chloroaniline; m-bromoaniline; p-ethoxyaniline; p-methoxyaniline; o-methylbenzylamine; m-methylbenzylamine; p-methylbenzylamine; p-methoxybenzylamine; o-chlorobenzylamine; m-chlorobenzylamine; and p-chlorobenzylamine. It should, however, be understood that this invention is not limited to the use of the above compounds only.
Novel compounds (I) according to this invention are prepared by, for example, the method referred to above. If necessary, the reaction may be carried out using a dehydrating agent such as dicycloalkylcarbodiimide or a basic catalyst such as alkali hydroxides, alkoxides, and amides.
Regarding the solvent for the reaction, alcohols such as methanol and ethanol, fatty or aromatic hydrocarbons such as n-hexane, benzene and xylene, halogenated hydrocarbons such as chloroform, cyclic ethers such as dioxane and tetrahydrofuran and aromatic heterocyclic compounds represented by pyridine can be used. The reaction may sometimes readily proceed without solvent, and in such case the solvent may be dispensed with.
Regarding the proportions of the materials used, 1.5 to 3 mols of the compound (II) are usually added to one mole of abietic acids of their active derivatives such as acid anhydride, ester and acid halide. If necessary, the acid component is dissolved or suspended in an adequate quantity of a suitable solvent, and the compound (II) is added by small quantities while executing requisite cooling and agitation of the system.
The reaction is carried out under a suitable temperature condition, for instance under ice cooling state, at room temperature or under heating, and is usually completed within 12 hours. Particularly the reaction between acid halide and compound (II) is completed at lower temperature within one hour, and this can be readily recognized from the disappearance of spots of material on a silica gel thin layer chromatogram.
After the termination of the reaction, the intended abietamide derivatives (I) such as AAN, DEAN, DIAN, TAN, ABA, DEBA, DIBA, and TBA can be separated from the reaction product mixture by the usual way. For example, where a hydrophilic solvent is used for reaction, the solvent is first removed under a reduced pressure condition, and a hydrophobic solvent such as ether and benzene is newly added. Then, the resultant system is washed. In case where a hydrophobic solvent such as benzene and n-hexane is used, the system is directly washed. The washing is made with a 3 to 5 percent dilute acid, if necessary, and then with a 3 to 5 percent dilute alkali and thereafter with water, followed by drying. After drying, the residual solvent is removed from the system, whereby crystalline particles as residue are obtained in many cases. In this case, purification through re-crystallization is directly made by using a suitable re-crystallizing solvent. Where the residue after the removal of solvent is oily, the purification is made with alumina or silica gel column chromatography or thin layer chromatography for manufacture.
While the DIA disclosed in the examples is Δ8 -dihydroabietic acid, this invention is not limited to the use of it only, but other Δ7 -, Δ13 -, and Δ14 -isomers are, of course, used as well.
The following examples are given to illustrate some representative embodiments of the invention. It is to be understood, however, that these examples are for the purpose of illustration only and not to be construed as a limit on the invention.
Examples 1 to 5 relate to manufacture of anilide derivatives or Formula 1 where M = 0 and Examples 6 to 10 to manufacture of benzylamine derivatives of Formula 1 whereM = 1.
EXAMPLE 1
N-(2,6-dimethylphenyl)-Δ8 -dihydroabietamide was produced in the following way:
Acid chloride obtained from 6.1 grams (20 millimols) of Δ8 -DIA and excessive thionyl chloride was cooled to freeze, and then 4.84 grams (20 millimols) of 2,6-dimethylaniline was added.
The resultant system was left at room temperature for one hour while intermittently agitating it. To the resultant liquid 50 millilitres of benzene was added to form a suspension, which was then washed with 5% HCl and then with water. Then, the benzene layer was dried with anhydrous magnesium sulfate, followed by removal of benzene. The resultant crystalline residue was re-crystallized from acetone to obtain 5.2 grams of colorless needle-like crystals (corresponding to a yield of 80 percent) with a melting point of 200° to 202° c.
Analysis of element: C28 H41 ON
______________________________________                                    
Analysis of element:  C.sub.28 H.sub.41 ON                                
           C          H           N                                       
______________________________________                                    
Calculated 82.50      10.14       3.44                                    
Found (%)  82.38      10.22       3.37                                    
______________________________________
EXAMPLE 2
N-(2,6-dimethylphenyl)-tetrahydroabietamide was produced in the following way:
Acid chloride obtained from 1.53 grams (5 millimols) of TA and excessive thionyl chloride was added to 10 millilitres of benzene, and to the resultant system 1.82 grams (15 millimols) of 2,6-dimethylaniline was gradually added. Then, the resultant system was continually agitated at room temperature for 2 hours, and then the precipitate was filtered away. Then, the resultant liquid was washed with 5-% HCl and then with water, and then the benzene layer was dried with anhydrous magnesium sulfate.
Then, benzene was removed to obtain a crystalline residue, which was then re-crystallized from acetone to obtain 16.8 grams of colorless needle-like crystals (corresponding to a yield of 82 percent) with a melting point of 218° to 220° C.
Analysis of element: C28 H43 ON
______________________________________                                    
Analysis of element:  C.sub.28 H.sub.43 ON                                
           C          H           N                                       
______________________________________                                    
Calculated (%)                                                            
           82.09      10.58       3.42                                    
Found (%)  82.13      10.45       3.60                                    
______________________________________
EXAMPLE 3
N-(p-ethoxyphenyl)-Δ8 -dihydroabietamide was produced in the following way:
Methylester obtained from 3.05 grams (10 millimols) of Δ8 -DIA and excessive diazomethane was added to 20 millilitres of xylene, and to the resultant system 2.8 grams (20 millimols) of p-ethoxyaniline and 830 milligrams (25 millimols) of sodium amide were added. The resultant liquid was filtered, and the filtrate was washed with 5-% HCl and then with water, and then the xylene layer was dried with anhydrous magnesium sulfate, followed by filtering. Then, xylene was removed under reduced pressure, and the crystalline residue powder was re-crystallized from methanol to obtain 17.8 grams of colorless needle-like crystals (corresponding to a yield of 42 percent) with a melting point of 136° to 138° C.
______________________________________                                    
Analysis of element:  C.sub.28 H.sub.41 O.sub.2 N                         
           C          H           N                                       
______________________________________                                    
Calculated (%)                                                            
           79.38      9.76        3.31                                    
Found (%)  79.44      9.51        3.12                                    
______________________________________
EXAMPLE 4
N-(p-methoxyphenyl)-abietamide was produced in the following way:
5.86 grams (10 millimols) of AA anhydride, 3.70 grams (30 millimols) of p-methoxy aniline and 50 millilitres of ethanol were mixed together, and the resultant liquid was agitated under heating for 2 hours. Then, ethanol was removed under reduced pressure. Then, 50 millilitres of ether was added, and the ether layer was washed with 3-% KOH aquaous solution, with 3-% HCl and then with water. Then, the resultant ether layer was dried with anhydrous magnesium sulfate, followed by filtering to remove ether. The resultant oily residue was left to crystallize. Then, by recrystallizing from ethanol 1.23 grams of colorless small needle-like crystals (corresponding to a yield of 60.6 percent) with a melting point of 134° to 136° C were obtained.
______________________________________                                    
Analysis of element:  C.sub.27 H.sub.37 O.sub.2 N                         
           C          H           N                                       
______________________________________                                    
Calculated (%)                                                            
           79.56      9.15        3.44                                    
Found (%)  79.60      9.16        3.18                                    
______________________________________
EXAMPLE 5
N-(p-chlorophenyl)-dehydroabietamide was produced in the following way:
3.00 grams (10 millimols) of DEA, 1.53 grams (12 millimols) of p-chloroaniline, 24.8 grams (12 millimols) of dicyclohexylcarbodiimide and 30 millilitres of dry dioxane were mixted together, and the resultant liquid was agitated at room temperature for 6 hours and then heated at 60° C for one hour. Then, the dioxane was removed through concentration under reduced pressure. Then, 150 millilitres of methylene chloride was added to the resultant residue, and the methylene chloride layer was washed with 3-% HCl and then with water, followed by drying with anhydrous sodium sulfate and filtering. The resultant filtrate was concentrated to 40 millilitres, followed by leaving overnight at room temperature. Then the precipitate was filtered away, and the filtrate was concentrated to dry solide. The powdery residue thus obtained was then re-crystallized from ethanol to obtain 3.03 grams of colorless needle-like crystals (corresponding to a yield of 74 percent) with a melting point of 180° to 181.5° C.
______________________________________                                    
Analysis of element:  C.sub.26 H.sub.32 ONCl                              
           C         H         N      Cl                                  
______________________________________                                    
Calculated (%)                                                            
           76.17     7.87      3.42   8.62                                
Found (%)  76.18     8.14      3.54   8.54                                
______________________________________
Similar to the above Examples 1 to 5, the following compound were also produced as further examples:
N-(2-Methylphenyl)-dihydroabietamide with a melting point of 164°-166° C
N-(2-Ethylphenyl)-dihydroabietamide with a melting point of 167°-169° C
N-(2,6-dimethylphenyl)-dehydroabietamide with a melting point of 227° to 229° C
N-(2,4-dimethylphenyl)-dihydroabietamide with a melting point of 148° to 150° C
N-(2,6-Diethylphenyl)-dihydroabietamide with a melting point of 219° to 221° C
N-(o-ethoxycarbonylphenyl)-dihydroabietamide which is oily
N-(p-methoxycarbonylphenyl)-dihydroabietamide with a melting point of 152° to 154° C
N-(3-hydroxy-4-carboxyphenyl)-dihydroabietamide with a melting (or decomposing) point of 260° C
N-(m-trifluoromethylphenyl)-dihydroabietamide with a melting point of 137° to 138° C
N-(m-bromophenyl)-dihydroabietamide with a melting point of 107° to 109° C
N-(p-nitrophenyl)-dihydroabietamide which is oily
N-(m-methoxyphenyl)-dihydroabietamide with a melting point of 149° to 152° C
N-(2,4,6-trimethylphenyl)-dihydroabietamide with a melting point of 215° to 217° C
EXAMPLE 6
N-(2-methylbenzyl)-Δ8 -dihydroabietamide was produced in the following way:
Acid chloride obtained from 1.53 grams (5 millimols) of Δ8 -DIA and excessive thionyl chloride was dissolved in 10 millilitres of benzene, and to this solution a solution obtained by dissolving 1.87 grams (15 millimols) of o-methylbenzylamine in 10 millilitres of benzene was added under cooling condition. The resultant system was the agitated at room temperature for 1.5 hours. The resultant liquid was then washed with 5-% HCI, water and with 5-% sodium hydroxide aqueous solution in the mentioned order. Then, the benzene layer was dried with anhydrous magnesium sulfate, followed by removal of benzene. The resultant crystalline residue was re-crystallized from acetone to obtain 1.69 grams of colorless planar crystals (corresponding to a yield of 83 percent) with a melting point of 121° to 122° C.
______________________________________                                    
Analysis of element:  C.sub.28 H.sub.41 ON                                
           C          H           N                                       
______________________________________                                    
Calculated (%)                                                            
           82.50      10.14       3.44                                    
Found (%)  82.45      10.29       3.52                                    
______________________________________
EXAMPLE 7
N-(3-chlorobenzyl)-Δ8 -dihydroabietamide was produced in the following way: Acid chloride obtained from 1.53 grams (5 millimols) of Δ8 -DIA and excessive thionyl chloride was dissolved in 10 millilitres of benzene, and to this solution a solution obtained by dissolving 2.12 grams (15 millimols ) of m-chlorobenzylamine in 10 millilitres of benzene was added under cooling condition. The resultant system was then agitated at room temperature for 3 hours. The resultant liquid was then treated in the same manner as in Example 6, and through re-crystallization from methanol 1.68 grams of colorless needle-like crystals (corresponding to a yield of 79 percent) with a melting point of 116° to 117° C were obtained.
______________________________________                                    
Analysis of element:  C.sub.27 H.sub.38 ONCI                              
           C         H         N      Cl                                  
______________________________________                                    
Calculated (%)                                                            
           75.76     8.94      3.27   8.28                                
Found (%)  75.72     9.05      3.47   8.30                                
______________________________________
EXAMPLE 8
N-(4-methoxybenzyl)-abietamide was produced in the following way:
5.89 grams (10 millimols) of AA anhydride, 3.42 grams (25 millimols) of p-methoxybenzylamine and 50 millilitres of ethanol were mixed together, and the resultant liquid was agitated while heating for 1.5 hours. Then, ethanol was removed under reduced pressure, and then 50 millilitres of ether was added.
The ether layer thus formed was then washed with 3-% KOH aqueous solution, water and with 3-% HCI in the mentioned order, and then it is dried with anhydrous magnesium sulfate, followed by removal of ether through filtering. The resultant oily residue was subjected to silica gel column chromatography with chloroform used as solvent to obtain 4.22 grams of glassy substance (corresponding to a yield of 72 percent).
______________________________________                                    
Analysis of element:  O.sub.23 H.sub.39 O.sub.2 N                         
           C          H           N                                       
______________________________________                                    
Calculated (%)                                                            
           79.76      9.32        3.32                                    
Found (%)  79.68      9.27        3.40                                    
______________________________________
EXAMPLE 9
N-(2-methylbenzyl)-tetrahydroabietamide was produced in the following way:
3.06 grams (10 millimols) of TA, 1.50 grams (12 millimols) of p-methylbenzylamine, 2.48 grams (12 millimols) of dicyclohexylcarbodiimide and 30 millilitres of dry dioxane were mixed together, and the resultant liquid was agitated at room temperature for 6 hours and then heated at 60° C for one hour. Then, the dioxane was removed through concentration under reduced pressure, and 150 millilitres of methylene chloride was added to the residue. The methylene chloride layer thus formed was then washed with 3-% HCl and then with water and dried with anhydrous magnesium sulfate, followed by filtering. The filtrate was then concentrated to 40 millilitres, followed by leaving overnight at room temperature. Then, the precipitate was filtered away, and the filtrate was concentrated to dry solide. The crystalline residue thus obtained was re-crystallized from methanol to obtain 2.65 grams colorless needle-like crystals (corresponding to a yield of 65 percent) with a melting point of 159° to 161° C.
______________________________________                                    
Analysis of element:  C.sub.28 H.sub.43 ON                                
           C          H           N                                       
______________________________________                                    
Calculated (%)                                                            
           82.09      10.58       3.42                                    
Found (%)  82.14      10.58       3.58                                    
______________________________________
EXAMPLE 10
N-(4-methylbenzyl)-dehydroabietamide was produced in the following way:
Methylester obtained from 3.00 grams (10 millimols) of DEA and excessive diazomethane was added to 20 millilitres of xylene, and to the resultant system 2.74 grams (30 millimols) of p-methylbenzylamine and 830 milligrams (25 millimols) of sodium amide were added. The resultant liquid was sealed within a pressure-bearing tube and heated there at 180° C for 20 hours. The resultant liquid was then filtered, and the filtrate was washed with 5-% HCl and then with water. The xylene layer was then dried with anhydrous magnesium sulfate and then filtered, followed by removal of xylene under reduced pressure. The crystalline residue was then re-crystallized from methanol to obtain 1.78 grams of colorless needle-like crystals (corresponding to a yield of 44 percent) with a melting point of 124° to 126° C.
______________________________________                                    
Analysis of element:  C.sub.28 H.sub.37 ON                                
           C          H           N                                       
______________________________________                                    
Calculated (%)                                                            
           83.32      9.24        3.47                                    
Found (%)  83.29      9.33        3.50                                    
______________________________________
Similar to the above Example 6 to 10, the following compounds were also produced as further examples:
N-(3-methylbenzyl)-Δ8 -dihydroabietamide with a melting point of 105° to 110° C
N-(4-methylbenzyl)-Δ8 -dihydroabietamide with a melting point of 130° to 132° C
N-(4-methoxybenzyl)-Δ8 -dihydroabietamide with a melting point of 129° to 130° C
N-(2-chlorobenzyl)-Δ8 -dihydroabietamide with a melting point of 150° to 151° C
N-(4-chlorobenzyl)-Δ8 -dihydroabietamide with a melting point of 127° to 130° C
Compounds prepared according to this invention have a high activity of reducing cholesterol in blood, which can be proved by an experiment described below.
A completely synthetic diet containing 1% of cholesterol, 0.25% of sodium cholate and 0.0003%, 0.003%, and 0.03% of the test compound is given to a group of 6 male rats having a body weight of about 50 g consecutively for 3 days, and the rats are fasted overnight. Then, the rats are decapitated and blood is collected to determine the cholesterol concentration in blood. The concentration of cholesterol in blood is measured with Technicon Autoanalyzer(Technicon Laboratory: Method File N-24a) Obtained results are shown in Table 1.
              Table 1                                                     
______________________________________                                    
                 % Inhibition                                             
Compound         Dose in Diet                                             
______________________________________                                    
                 0.0003%   0.003%    0.03%                                
N-(m-Bromophenyl)-dihydro-                                                
abietamide       7         23*       60**                                 
N-(2,6-Dimethylphenyl)-Δ.sup.8 -                                    
dihydroabietamide                                                         
                 33**      76**      102**                                
N-(2,4,6-Trimethylphenyl)-                                                
dihydroabietamide                                                         
                 21**      54**      70**                                 
N-(4-Chlorobenzyl)-Δ.sup.8 -                                        
dihydroabietamide                                                         
                 --        9         30**                                 
______________________________________
Each value shown in the Table is a relative value determined based on the supposition that the value of the control group (the cholesterol-administered group) is 0 and the value of the normal group (the non-cholesterol-administered group) is 100. The mark "*" indicates that the value is statistically significant over the control group with a significant level of 5% and the mark "*" indicates that the value is statistically significant over the control group with a significance level of 1%.
From the results shown in the Table, it will readily be understood that each compound has a significant effect of reducing cholesterol in blood even when it is administered in a very minute amount and is very valuable as an anti-arteriosclerotic agent.

Claims (15)

What is claimed is:
1. An N-(substituted phenyl) or N-(substituted benzylamide of an acid selected from the group consisting of abietic, dehydroabietic, dihydroabietic and tetrahydroabietic acids wherein said phenyl or benzyl is substituted with from one to three substituents independently selected from the group consisting of halo, nitro, lower alkyl, haloalkyl, hydroxyl, lower alkoxy, carboxyl or carbalkoxy.
2. An amide according to claim 1 wherein said substituted phenyl is chlorophenyl, bromophenyl, nitrophenyl, methylphenyl, dimethylphenyl, trimethylphenyl, ethylphenyl, diethylphenyl, trifluoromethylphenyl, methoxyphenyl, ethoxyphenyl, hydroxy-carboxyphenyl, carbomethoxyphenyl or carbethoxyphenyl.
3. The amide of abietic acid, dehydroabietic acid, Δ8 -dihydroabictic acid or tetrahydroabietic acid according to claim 3.
4. An amide according to claim 1 wherein said substituted benzyl is chlorobenzyl, methylbenzyl, or methoxybenzyl.
5. The amide of abietic acid, dehydroabietic acid, Δ8 -dihydroabietic acid or tetrahydroabietic acid according to claim 4.
6. The amide according to claim 1 which is N-(2,6-dimethylphenyl)-Δ8 -dihydroabietamide.
7. The amide according to claim 1 which is N-(2,6-dimethylphenyl)-tetrahydroabietamide.
8. The amide according to claim 1 which is N-(p-ethoxyphenyl)-Δ8 -dihydroabietamide.
9. The amide according to claim 1 which is N-(p-methoxyphenyl)-abietamide.
10. The amide according to claim 1 which is N-(p-chlorophenyl)-dehydroabietamide.
11. The amide according to claim 1 which is N-(2-methylbenzyl)-Δ8 -dihydroabietamide.
12. The amide according to claim 1 which is N-(3-chlorobenzyl)-Δ8 -dihydroabietamide.
13. The amide according to claim 1 which is N-(4-methoxybenzyl)-abietamide.
14. The amide according to claim 1 which is N-(2-methylbenzyl)-tetrahydroabietamide.
15. The amide according to claim 1 which is N-(4-methylbenzyl)-dehydroabietamide.
US05/604,308 1974-08-28 1975-08-13 N-(substituted phenyl and benzyl)abietamides Expired - Lifetime US4009206A (en)

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DE3704404A1 (en) * 1986-02-15 1987-08-20 Nippon Shinyaku Co Ltd LIQUID AMID DERIVATIVES
US20060252832A1 (en) * 1999-05-14 2006-11-09 Michael Palladino Novel interleukin-1 and tumor necrosis factor-alpha modulators, synthesis of said modulators and their enantiomers and methods of using said modulators
WO2007015757A3 (en) * 2005-07-21 2007-06-21 Nereus Pharmaceuticals Inc Interleukin-1 and tumor necrosis factor-a modulators; syntheses of such modulators and methods of using such modulators
US7342125B2 (en) 1999-05-14 2008-03-11 Nereus Pharmaceuticals, Inc. Method of treating inflammation with acanthoic acid derivatives
CN103073444A (en) * 2013-01-28 2013-05-01 中国林业科学研究院林产化学工业研究所 Application of dehydroabietic acid based arylamine compound as hole transport material

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FR2781802B1 (en) * 1998-07-31 2001-05-11 Bio Merieux SATURATED OR UNSATURATED DERIVATIVES OF ABIETANE, CONJUGATES DERIVATIVES AND USES IN A DIAGNOSTIC COMPOSITION, A REAGENT AND A DEVICE
US6831101B2 (en) * 2001-06-14 2004-12-14 Chemokine Therapeutics Corporation Tricyclic rantes receptor ligands
CN115819268A (en) * 2022-08-22 2023-03-21 浙江工业大学 C-14 amide substituted dehydroabietic acid derivatives, and preparation method and application thereof

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US3281453A (en) * 1961-03-23 1966-10-25 Hooker Chemical Corp N-(decachloro-3-hydroxypentacyclo (5.3.0.02, 6.04, 10.05, 9)decyl-3) amides

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3704404A1 (en) * 1986-02-15 1987-08-20 Nippon Shinyaku Co Ltd LIQUID AMID DERIVATIVES
US20080188475A1 (en) * 1999-05-14 2008-08-07 Nereus Phamaceuticals, Inc. Novel Interleukin-1 and Tumor Necrosis Factor-Alpha Modulators, Syntheses of Said Modulators and Their Enantiomers and Methods of Using Said Modulators
US7288671B2 (en) 1999-05-14 2007-10-30 Nereus Pharmaceuticals, Inc. Interleukin-1 and tumor necrosis factor-α modulators, synthesis of said modulators and their enantiomers and methods of using said modulators
US7342125B2 (en) 1999-05-14 2008-03-11 Nereus Pharmaceuticals, Inc. Method of treating inflammation with acanthoic acid derivatives
US20080103328A1 (en) * 1999-05-14 2008-05-01 Nereus Pharmaceuticals, Inc. Novel Interleukin-1 and Tumor Necrosis Factor-Alpha Modulators, Syntheses of Said Modulators and Their Enantiomers and Methods of Using Said Modulators
US20060252832A1 (en) * 1999-05-14 2006-11-09 Michael Palladino Novel interleukin-1 and tumor necrosis factor-alpha modulators, synthesis of said modulators and their enantiomers and methods of using said modulators
WO2007015757A3 (en) * 2005-07-21 2007-06-21 Nereus Pharmaceuticals Inc Interleukin-1 and tumor necrosis factor-a modulators; syntheses of such modulators and methods of using such modulators
US7893299B2 (en) 2005-07-21 2011-02-22 Nereus Pharmaceuticals, Inc. Interleukin-1 and tumor necrosis factor-αmodulators; syntheses of such modulators and methods of using such modulators
US20110160309A1 (en) * 2005-07-21 2011-06-30 Nereus Pharmaceuticals, Inc. Interleukin-1 and tumor necrosis factor-alpha modulators; syntheses of such modulators and methods of using such modulators
US8133915B2 (en) 2005-07-21 2012-03-13 Nereus Pharmaceuticals, Inc. Interleukin-1 and tumor necrosis factor-α modulators; syntheses of such modulators and methods of using such modulators
AU2006276274B2 (en) * 2005-07-21 2012-03-29 Nereus Pharmaceuticals, Inc. Interleukin-1 and tumor necrosis factor-a modulators; syntheses of such modulators and methods of using such modulators
CN103073444A (en) * 2013-01-28 2013-05-01 中国林业科学研究院林产化学工业研究所 Application of dehydroabietic acid based arylamine compound as hole transport material
CN103073444B (en) * 2013-01-28 2015-04-01 中国林业科学研究院林产化学工业研究所 Application of dehydroabietic acid based arylamine compound as hole transport material

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